Inflammation is normally an acute response by the immune system to invasion by microbial pathogens, chemicals or physical injury. In some cases, however, the inflammatory response can progress to a chronic state, and be the cause of inflammatory disease. Therapeutic control of this chronic inflammation in diverse diseases is a medical need.
Leukotrienes (LT) are biologically active metabolites of arachidonic acid (B. Samuelsson, Science 1983, 220(4597): 568-575) that have been implicated in inflammatory diseases, including asthma (D. A. Munafo et al., J. Clin. Invest. 1994, 93(3): 1042-1050; N. Miyahara, et al., Allergol Int., 2006, 55(2): 91-7; E. W. Gelfand, et al., J. Allergy Clin. Immunol. 2006, 117(3): 577-82; K. Terawaki, et al., J. Immunol. 2005, 175(7): 4217-25), inflammatory bowel disease (IBD) (P. Sharon and W. F. Stenson, Gastroenterology 1984, 86(3): 453-460), chronic obstructive pulmonary disease (COPD) (P. J. Barnes, Respiration 2001, 68(5): 441-448), arthritis (R. J. Griffiths et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92(2): 517-521; F. Tsuji et al., Life Sci. 1998, 64(3): L51-L56), psoriasis (K. Ikai, J. Dermatol. Sci. 1999, 21(3): 135-146; Y. I. Zhu and M. J. Stiller, Skin Pharmacol. Appl. Skin Physiol. 2000, 13(5): 235-245) and atherosclerosis (Friedrich, E. B. et al. Arterioscler Thromb Vasc Biol 23, 1761-7 (2003); Subbarao, K. et al. Arterioscler Thromb Vasc Biol 24, 369-75 (2004); Helgadottir, A. et al. Nat Genet. 36, 233-9 (2004); Jala, V. R. et al Trends in Immun. 25, 315-322 (2004)). The synthesis of leukotrienes is initiated by the conversion of arachidonic acid to an unstable epoxide intermediate, leukotriene A4 (LTA4), by 5-lipoxygenase (5-LO) (A. W. Ford-Hutchinson et al., Annu. Rev. Biochem. 1994, 63: 383-347). This enzyme is expressed predominantly by cells of myeloid origin, particularly neutrophils, eosinophils, monocytes/macrophages and mast cells (G. K. Reid et al., J. Biol. Chem. 1990, 265(32): 19818-19823). LTA4 can either be conjugated with glutathione by leukotriene C4 (LTC4) synthase to produce the cysteinyl leukotriene, LTC4, or hydrolyzed to the diol, leukotriene B4 (LTB4) (B. Samuelsson, Science 1983, 220(4597): 568-575). LTC4 and its metabolites, LTD4 and LTE4, induce smooth muscle contraction, broncho-constriction and vascular permeability, while LTB4 is a potent chemo-attractant and activator of neutrophils, eosinophils, monocytes/macrophages, T cells and mast cells.
The stereospecific hydrolysis of LTA4 to LTB4 is catalyzed by leukotriene A4 hydrolase (LTA4H), a zinc-containing cytosolic enzyme. This enzyme is ubiquitously expressed with high levels in small intestinal epithelial cells, lung, and aorta (B. Samuelsson and C. D. Funk, J. Biol. Chem. 1989, 264(33): 19469-19472). Moderate expression of LTA4H is observed in leukocytes, particularly neutrophils (T. Yokomizo et al., J. Lipid Mediators Cell Signalling 1995, 12(2,3): 321-332).
Leukotriene B4 is a key pro-inflammatory lipid mediator, able to recruit and activate inflammatory cells, such as neutrophils, eosinophils, monocytes/macrophages, T cells and mast cells (F. A. Fitzpatrick et al., Ann. N.Y. Acad. Sci. 1994, 714: 64-74; S. W. Crooks and R. A. Stockley, Int. J. Biochem. Cell Biol. 1998, 30(2): 173-178; A. Klein et al., J. Immunol. 2000, 164: 4271-4276). LTB4 mediates its pro-inflammatory effects by binding to G protein-coupled receptors, leukotriene B4 receptor 1 (BLT1) and leukotriene B4 receptor 2 (BLT2) (T. Yokomizo et al., Arch. Biochem. Biophys. 2001, 385(2): 231-241). The receptor first identified, BLT1, binds LTB4 with high affinity, leading to intracellular signaling and chemotaxis. BLT1 is expressed mainly in peripheral leukocytes, particularly neutrophils, eosinophils, macrophages (Huang, W. W. et al. J Exp Med 188, 1063-74 (1998)) and monocytes (Yokomizo, T., Izumi, T. & Shimizu, T. Life Sci 68, 2207-12 (2001)). The murine receptor is also expressed on effector T cells and was recently shown to mediate LTB4-dependent migration of effector CD8+ T cells (Goodarzi, K., Goodarzi, M., Tager, A. M., Luster, A. D. & von Andrian, U. H. Nat Immunol 4, 965-73 (2003); Ott, V. L., Cambier, J. C., Kappler, J., Marrack, P. & Swanson, B. J. Nat Immunol 4, 974-81 (2003)), early effector CD4+T helper type 1 (TH1) and TH2 chemotaxis and adhesion to endothelial cells, as well as early effector CD4+ and CD8+ T cell recruitment in an asthma animal model (Tager, A. M. et al., Nat Immunol 4, 982-90 (2003)). LTB4 receptor BLT2 (S. Wang et al., J. Biol. Chem. 2000, 275(52): 40686-40694; T. Yokomizo et al., J. Exp. Med. 2000, 192(3): 421-431) shares 42% amino acid homology with BLT1, but is more broadly expressed, including in peripheral tissues such as the spleen, ovary and liver, as well as in leukocytes. BLT2 binds LTB4 with lower affinity than BLT1 does, mediates chemotaxis at higher concentrations of LTB4, and differs from BLT1 in its affinity for certain antagonists. While LTB4 receptor antagonists may differ in their affinity for BLT1 versus BLT2, blocking the production of LTB4 using LTA4H inhibitors would be expected to inhibit the downstream events mediated through both BLT1 and BLT2.
Studies have shown that introduction of exogenous LTB4 into normal tissues can induce inflammatory symptoms (R. D. R. Camp et al., Br. J. Pharmacol. 1983, 80(3): 497-502; R. Camp et al., J. Invest. Dermatol. 1984, 82(2): 202-204). Increased production of LTB4 is considered important for the inflammatory component in a number of diseases, including atopic dermatitis (O. Koro et al. J. Allergy Clin. Immunol. 1999, 103, 663-670), asthma (M. Frieri et al., Ann. Allergy Asthma Immunol. 1998, 81, 331-336), inflammatory bowel disease, chronic obstructive pulmonary disease (W. A. Biernacki et al. Thorax 2003, 58, 294-298; J. S. Seggev et al., Chest 1991, 99, 289-291), atherosclerosis and cardiovascular disease, multiple sclerosis (I. S. Neu et al., Acta Neurol. Scand. 2002, 105, 63-66), psoriasis (D. M. Reilly, Acta Derm. Venereol. 2000, 80, 171-174), cystic fibrosis (J. T. Zakrzewski, et al., Br J Clin Pharmacol 1987, 23:19-27), and rheumatoid arthritis (N. Ahmadzadeh, Inflammation 1991, 15, 497-503). Therefore, inhibitors of LTB4 production should have therapeutic value as anti-inflammatory agents for these conditions. Thus, reduction of LTB4 production by an inhibitor of LTA4H activity would be predicted to have therapeutic potential in a wide range of diseases.
This idea is supported by a study of LTA4H-deficient mice that, while otherwise healthy, exhibited markedly decreased neutrophil influx in arachidonic acid-induced ear inflammation and zymosan-induced peritonitis models (R. S. Byrum et al., J. Immunol. 1999, 163(12): 6810-6819). LTA4H inhibitors have been shown to be effective anti-inflammatory agents in pre-clinical studies. For example, oral administration of LTA4H inhibitor SC57461 caused inhibition of ionophore-induced LTB4 production in mouse blood ex vivo, and in rat peritoneum in vivo (J. K. Kachur et al., J. Pharm. Exp. Ther. 2002, 300(2), 583-587). Eight weeks of treatment with the same inhibitor compound significantly improved colitis symptoms in cotton top tamarins (T. D. Penning, Curr. Pharm. Des. 2001, 7(3): 163-179). The spontaneous colitis that develops in these animals is very similar to human IBD. The results therefore indicate that LTA4H inhibitors would have therapeutic utility in this and other human inflammatory diseases.
Events that elicit the inflammatory response include the formation of the pro-inflammatory mediator leukotriene B4. Hydrolase LTA4H catalyzes the formation of this mediator, and LTA4H inhibitors block the production of the pro-inflammatory mediator LTB4, thus providing the ability to prevent and/or treat leukotriene-mediated conditions, such as inflammation. The inflammatory response is characterized by pain, increased temperature, redness, swelling, or reduced function, or by a combination of two or more of these symptoms. Regarding the onset and evolution of inflammation, inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.
Compounds of the present invention were shown to inhibit LTA4H in in vitro assays. Inhibition was shown in a recombinant enzymatic assay containing the human LTA4 hydrolase and in a cellular assay using murine blood (diluted 1 in 15). Embodiments of the invention were also shown to inhibit murine ex vivo LTB4 production in whole blood (diluted 1:1), as well as arachidonic acid-induced neutrophil influx in murine ear tissue.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that usually occurs in individuals with a personal or family history of atopy. The major features are pruritus and chronic or relapsing eczematous lesions. Complications include bacterial, fungal and viral infections as well as ocular disease. Atopic dermatitis is the most common inflammatory skin disease in children and affects more than 15% of children in the US (Laughter, D., et al., J. Am. Acad. Dermatol. 2000, 43, 649-655). Atopic dermatitis may persist in 60% of adults who were affected as children (Sidbury, R., et al., Dermatol. Clin. 2000, 18(1), 1-11).
Atopic dermatitis has significant societal impact. The family stress related to caring for children with moderate to severe AD may be comparable to the stress seen in families of children with type I diabetes mellitus (Su, J. C., et al., Arch. Dis. Child 1997, 76, 159-162). In the US, the annual cost of medical services and prescription drugs for the treatment of AD/eczema is similar to those for emphysema, psoriasis and epilepsy (Ellis, C. N., et al., J. Am. Acad. Dermatol. 2002, 46, 361-370).
Several lines of evidence support the role of LTB4 in AD. LTB4 levels are elevated in skin lesions (K. Fogh et al., J. Allergy Clin. Immunol. 1989, 83, 450-455; T. Ruzicka et al., J. Invest. Dermatol. 1986, 86, 105-108) and plasma in AD, and contribute to the inflammation through chemotactic effects on inflammatory cells (Wedi and Kapp BioDrugs. 2001; 15, 729-743). Reported in vivo and in vitro studies have shown that leukotrienes, especially LTB4, contribute to the inflammation of the skin in AD through their chemotactic effect on inflammatory cells. LTB4 receptors are expressed on mast cells, T cells, eosinophils, dendritic cells and macrophages, all of which accumulate in AD lesions. LTB4 itself is a pruritic agent, and has also been shown to mediate substance P-induced pruritus (T. Andoh et al., J. Invest. Dermatol. 2001, 117, 1621-1626), a key component of the itching in AD (T. Ohmura et al., Eur. J. Pharmacol. 2004, 491, 191-194). LTB4 induces proliferation of keratinocytes, an effect that is further potentiated by substance P (M. J. Rabier et al., J. Invest. Dermatol. 1993, 110, 132-136). Recent reports indicate a role for LTB4 in development of a Th2 immune response and IgE production. The role of LTB4 in AD is supported by beneficial effects of the 5-lipoxygenase inhibitor, zileuton, in a small, open-label clinical trials of AD (Woodmansee et al., Ann. Allergy Asthma Immunol. 1999, 83, 548-552) and in relieving the pruritus in Sjogren-Larsson syndrome patients who have elevated LTB4 due to an impairment in its degradation (Willemsen et al., Eur. J. Pediatr. 2001, 160, 711-717).
While AD that is mild to moderate in severity generally responds to topical therapy, correct use of these therapies and compliance remain a major issue in the clinic (T. Agner, Acta Derm. Verereol. Suppl. (Stockh) 2005, 213, 33-35). Topical corticosteroids and emollients are the standard of care in the treatment of AD. However, systemic immunomodulatory therapies and potent topical corticosteroids used to treat severe AD are associated with significant cutaneous side effects, such as striae, atrophy and telangeictasia that limit the long-term use of these agents (Hanifin et al., J. Am. Acad. Dermatol. 2004, 50, 391-404).
Emollients have a steroid-sparing effect and are useful for both prevention and maintenance therapy. Crude coal tar and preparations containing coal tar derivatives have also been used for many years in the treatment of AD and have significant cosmetic disadvantages that influence compliance (Hanifin, et al., 2004). Topical doxepin may be a useful short-term adjunctive therapy for the relief of pruritus but sedation and contact dermatitis may complicate its use (Hanifin, et al., 2004).
Tacrolimus (Protopic®) and pimecrolimus (Elidel®) are topical calcineurin inhibitors that have been shown to reduce the extent, severity and symptoms of AD in adults and children and are approved for use as second-line therapy of AD. However, the recent addition of boxed warnings to the product labels regarding rare cases of malignancy reported in patients treated with topical calcineurin inhibitors limits long term use of these agents in the treatment of AD (Food and Drug Administration [FDA]/Center for Drug Evaluation and Research [CDER] resources page).
Antibiotics are used in the treatment of Staphylococcus aureus infections in patients with AD but have a minimal effect on the dermatitis (Hanifin, et al., 2004). Although sedating antihistamines may be useful if sleep disruption is present, oral antihistamines are generally not effective in treating AD-associated pruritus (Hanifin, et al., 2004). Ultraviolet (UV) phototherapy, including photochemotherapy with psoralen is well established in the treatment of AD but relapse upon cessation of therapy frequently occurs (Hanifin, et al., 2004).
Systemic immunomodulatory therapy with cyclosporine and corticosteroids is effective but can be associated with severe side effects and is generally reserved for patients with severe disease. Systemic corticosteroids are associated with growth retardation in children, avascular necrosis of bone, osteopenia, increased risk of infection, poor wound healing, cataracts, hyperglycemia and hypertension. Cyclosporine is nephrotoxic in a majority of patients and is associated with tremor, hirsutism, hypertension, hyperlipidemia and gum hyperplasia.
While AD that is mild to moderate in severity generally responds to topical therapy, correct use of these therapies and compliance remain a major issue in the clinic. An oral or topical agent lacking the risks associated with corticosteroids and the calcineurin inhibitors would be a welcome addition to the armamentarium of treatments for AD that is mild to moderate in severity. An effective oral or topical therapy with fewer side effects than systemic immunomodulatory therapies and potent topical corticosteroids would fill an unmet medical need in the treatment of AD.
Sjogren-Larsson syndrome is an autosomal recessive neurocutaneous disorder with severe ichthyosis. It is caused by mutation of the gene encoding microsomal fatty aldehyde dehydrogenase (FALDH) leading to a defect in fatty alcohol metabolism. FALDH catalyzes the oxidation of medium- to long-chain fatty aldehydes to their corresponding carboxylic acids. LTB4, a pro-inflammatory mediator synthesized from arachidonic acid, is inactivated by microsomal omega-oxidation, successively yielding 20-OH-LTB4, 20-CHO-LTB4 and 20-COOH-LTB4. The urine of Sjogren-Larsson syndrome patients contains highly elevated levels of LTB4 and 20-OH-LTB4. Defective LTB4 degradation in Sjogren-Larsson syndrome patients is now considered to be shown with “unambiguous evidence” (Willemsen et al., J. Neurol. Sci. 2001, 183(1), 61-7). Sjogren syndrome is an autoimmune disease that features inflammation in some glands. Sjogren syndrome may feature also extraglandular manifestations. When the gland inflammation is not associated with another connective tissue disease, then the syndrome is referred to as primary Sjogren syndrome. When it is associated with a connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus or scleroderma, then it is referred to as secondary Sjogren syndrome. The term “Sjogren syndrome” herein refers to any one of the primary and secondary Sjogren syndromes. No cure is currently known for this syndrome. The current treatments usually focus on the specific area of the body that is affected and also in the treatment of associated complications. Immuno-suppressants such as cortisones, azathioprine and cyclophosphamide are sometimes used to threat some serious complications, and antibiotics are also used to treat associated infections.
Embodiments of this invention have shown dose-dependent inhibition of dermal inflammation in the arachidonic acid-induced murine ear inflammation model. Oral administration of embodiments of this invention dose-dependently inhibited neutrophil influx and edema, and were shown to inhibit the ex vivo ionophore-stimulated LTB4 production at doses between 0.3 and 30 mg/kg.
LTA4H inhibitors are hypothesized to specifically block the production of LTB4 from LTA4, without affecting the biosynthesis of lipoxins, which are also produced from LTA4. Increasing or maintaining lipoxin A4 (LXA4) production may have beneficial therapeutic effects in dermal inflammation as it has been reported that topical application of a stable lipoxin analogue inhibits edema, granulocyte infiltration and epidermal hyperproliferation in murine skin inflammation models. 5-LO inhibitors block the pathway upstream of LTA4. This would be expected to lead to a block in not only synthesis of LTA4, LTB4 and cysteinyl leukotrienes (CysLT), but also LXA4.
Asthma is a chronic disease characterized by a variable degree of airflow obstruction, bronchial hyperresponsiveness and airway inflammation (Busse & Lemanske, 2001). Immunohistopathologic features include denudation of airway epithelium, collagen deposition beneath basement membrane, edema, mast cell activation, and inflammatory cell infiltration by neutrophils (especially in sudden-onset, fatal asthma exacerbations), eosinophils, and Th2 lymphocytes (Busse et al., N. Engl. J. Med. 2001, 344, 350-362). Airway inflammation contributes to the airway hyperresponsiveness, airflow limitation (acute bronchoconstriction, airway edema, mucus plug formation and airway wall remodeling, leading to bronchial obstruction), respiratory symptoms and disease chronicity (NIH Guidelines for the Diagnosis and Management of Asthma 1997).
Current therapy for asthma is directed at controlling acute bronchoconstrictive symptoms with beta2-adrenergic receptor agonists and managing underlying airway inflammation with inhaled corticosteroids, chromates such as cromolyn sodium and nedocromil, and antileukotriene agents, such as the cysteinyl leukotriene receptor antagonists montelukast and zafirlukast and the 5-lipoxygenase inhibitor zileuton. Systemic steroids are used in severe disease and acute exacerbations of asthma. The humanized monoclonal anti-IgE antibody omalizumab was approved for the treatment of patients with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids (XOLAIR® [omalizumab] July 2007).
The inflammatory component of mild persistent and moderate asthma can generally be controlled with inhaled corticosteroids, but patient compliance remains a major issue in disease management (H. Milgrom et al., J. Allergy Clin. Immunol. 1996, 98, 1051-1057). Despite optimum therapy, including long-acting beta-agonists and inhaled corticosteroids, many patients have poorly controlled asthma (Fitzgerald et al., Can. Respir. J. 2006, 13, 253-259; Bellamy et al., Prim. Care Respir. J. 2005, 14, 252-258). Severe asthma requires treatment with high-dose inhaled steroids or the frequent use of oral corticosteroids (Moore et al., J. Allergy Clin. Immunol. 2006, 117, 487-494), both of which can be associated with negative side effects such as osteopenia and growth retardation in children (Allen et al., Suppl. J. Allergy Clin. Immunol., 2003, 112, 51; Schimmer et al., Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Action of Adrenocortical Hormones in Hardman J G, Limbird L E; eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill; 2001; 1666-1668). An oral therapy that could effectively treat moderate-to-severe asthma and reduce corticosteroid requirements would address unmet medical needs.
Leukotrienes are important mediators in asthma pathogenesis and comprise two classes—the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) and LTB4. Leukotriene receptor antagonists, such as montelukast or zafirlukast, target only the cysteinyl leukotrienes, while 5-lipoxygenase inhibitors, such as zileuton, inhibit the pathway upstream of both classes, and thus decrease formation of both the cysteinyl leukotrienes and LTB4. LTA4H inhibitors selectively inhibit LTB4 synthesis and do not impact cysteinyl leukotriene (CysLT) synthesis. Both classes of leukotrienes are elevated in asthma, and LTB4 is more significantly increased in severe asthma, which is associated with increased neutrophilic inflammation.
Several preclinical and clinical findings suggest that inhibition of LTB4 synthesis by LTA4H inhibitors will have therapeutic benefit in asthma. Studies in mice lacking LTB4 receptors have shown that LTB4 plays a role in eosinophil and effector T cell recruitment, IL-13 production, goblet cell hyperplasia and mucus secretion, IgE production and airway hyperreactivity (Miyahara et al., Allergy Intl. 2006, 55, 91-97). The importance of LTB4 in development in airway hyperreactivity is supported by data with the LTB4 receptor antagonist (CP-105,696), which reduced airway hyperresponsiveness induced by multiple antigen challenges in a primate model (Turner et al., J. Clin. Invest. 1996, 97, 381-387). Furthermore, the reduction of bronchial hyperresponsiveness in human asthma by the 5-LO inhibitor, zileuton, has been attributed to its inhibition of LTB4 synthesis (Dahlen et al., Eur. J. Pharmacol. 2006, 533(1-3), 40-56). Inhibition of LTB4 may also be beneficial in severe asthma (Wenzel et al., Am. J. Respir. Grit. Care Med., 1997, 156, 737-743) and viral exacerbations of asthma (S.D. Message, Eur. Respir. J., 2001, 18, 1013-1025), where neutrophilic inflammation is more prominent. CysLT antagonists and steroids have limited efficacy in severe asthmatics, while zileuton has been shown to significantly improve quality of life in these patients (R. Menendez et al., American Thoracic Society Meeting, San Diego, 2006).
An allergy is an abnormal reaction to an allergen (an ordinarily harmless substance) that triggers an abnormal response in a sensitized individual. Allergic rhinitis is an inflammation of the mucus membranes of the nose that occurs in response to an airborne antigen (allergen). Allergic rhinitis, also called allergic rhinoconjunctivitis, is characterized by frequent or repetitive sneezing, runny or congested nose, and pruritus of the nose, eyes and throat. It may also be associated with other symptoms such as headache, impaired smell, postnasal drip, conjunctival symptoms (e.g., itchy watery eyes), sinusitis and other complicating respiratory symptoms. Depending upon the time of exposure, allergic rhinitis can be classified as perennial, seasonal or occupational.
Based upon the well-described leukotriene biosynthesis pathway, LTA4H inhibitors are hypothesized to specifically block the production of LTB4 from LTA4, without affecting the biosynthesis of lipoxins, which are also produced from LTA4. Lipoxins, such as LXA4, have been the focus of intense study and are known to play a key role as natural anti-inflammatory agents and key mediators of the natural process of resolving an inflammatory response. Furthermore, production of endogenous LXA4 has been described in a variety of inflammatory diseases and lower levels of LXA4 have been found in patients with severe versus moderate asthma. These data are consistent with the proposition that LXA4 plays an important role in resolution of acute inflammation. Unlike LTA4H inhibitors, 5-LO inhibitors block this pathway upstream of LTA4. This would lead to a block in not only synthesis of LTA4, LTB4 and cysteinyl leukotrienes, but also LXA4. Furthermore, there is a possibility that LTA4H inhibitors result in a buildup of LTA4, and pathway shunting to pro-inflammatory cysteinyl leukotrienes, although to date there is no known data to support this possibility.
Neutrophil infiltration is a prominent feature of severe asthma. Zileuton (Zyflo®), which targets both LTB4 and cysteinyl leukotrienes, has been suggested to be efficacious in severe asthma patients, while CysLT antagonists (for example, Montelukast/Singulair®), which target only cysteinyl leukotrienes, show limited efficacy. Combination of an LTA4H inhibitor and at least one of a CysLT receptor antagonist (for example, Montelukast/Singulair®) and LTC4 synthase inhibitor would target both LTB4 and cysteinyl leukotrienes, while leaving production of the anti-inflammatory lipoxins intact. Embodiments of this invention are envisioned to reduce inflammatory responses to airway allergen challenge, leading to dose-dependent decreases in airway recruitment of inflammatory cells.
Embodiments of this invention are expected to find utility in treating inflammatory bowel disease. In trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, LTA4H inhibition had significant inhibitory effects on colonic inflammation, including macroscopic colonic injury, inflammatory cell content, and levels of tumor necrosis factor alpha (TNF-α), LTB4, and IL-6 (Whittle et al., Br J. Pharmacol., 2008, 153, 983-991). LTA4H inhibition reportedly also significantly attenuated the joint inflammation and swelling associated with the destruction of collagen in murine models of arthritis. Mice deficient in receptors for LTB4 or lacking LTA4H do not develop arthritis in murine models (Mathis, S., et al. Role of leukotriene B4 receptors in rheumatoid arthritis, Autoimmun. Rev., 2007 Nov., 7(1):12-7). Embodiments of this invention are thus expected to find utility in treating arthritis, including, but not limited to, rheumatoid arthritis.
Abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta that exceeds the normal diameter (2 cm) by more than 50%. It is caused by a degenerative process of the aortic wall. An aortic aneurysm may also occur in the thorax. Surgery is eventually required to prevent the progression to AAA rupture, which is most often a fatal event. Thus therapeutics which delay or prevent the need for surgery are an unmet medical need.
Recent genetic studies in humans as well as studies in mice and rabbits have implicated the leukotriene synthesis pathway in cardiovascular disease (reviewed in Whatling et al., Expert Opin Investig Drugs 2007, 16(12), 1879-93). In a well-established murine abdominal aortic aneurysm (AAA) model, mice that lack the receptor for LTB4 exhibit a reduced incidence of AAA formation (Ahluwalia et al., J. Immunol. 2007, 179(1), 691-7). Diminished AAA formation in LTB4-receptor-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, it has been shown that signaling by LTB4 through its receptor contributes to the frequency and size of abdominal aortic aneurysms in mice, and prevention of LTB4 signaling by deletion of the gene coding for the LTB4 receptor in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. Thus LTB4 signaling is a target for intervention in modulating development of aortic aneurysms. Inhibitors of LTA4H in the context of this invention are expected to have utility in inhibition of aortic aneurysms.
Adiposity-associated inflammation and insulin resistance are associated with the development of type II diabetes and atherosclerosis. Macrophages are recruited into adipose tissue and atherosclerotic plaques, and are activated to release inflammatory cytokines and chemokines. In particular, MCP-1 has been shown to play a role in macrophage infiltration into adipose tissue. Leukotriene B4 is a potent pro-inflammatory lipid mediator which is a chemoattractant for inflammatory leukocytes including monocytes and macrophages. In addition, LTB4 has been shown to induce MCP-1 production by monocytes, thus potentially amplifying accumulation and activation of macrophages in adipose tissue and atherosclerotic plaques. LTA4H is an enzyme in the 5-lipoxygenase pathway which catalyzes the rate-limiting step in the production of LTB4. This pathway is amplified in atherosclerotic lesions of diabetic patients and is genetically linked to cardiovascular disease. Thus inhibitors of LTA4H may have beneficial therapeutic effects in metabolic disorders through reduction of inflammation.
LTB4 release in the alveoli has been implicated in emphysema of α1-antitrypsin (α1AT) deficiency (R. C. Hubbard, et al., J. Clinical Investigation 1991, 88, 891-97). Consequently, LTA4H inhibitors may have beneficial therapeutic effects in the treatment or prevention of emphysema of α1AT deficiency.
The effect of the administration of an LTA4H inhibitor, such as the compound in example 150 in U.S. Patent Appl. Publ. No. US2005/0043378, was tested in the context of this invention in the treatment of insulin resistance in the DIO mouse model. LTA4H inhibitor administration (10 mg/kg PO) significantly reduced fed and fasted glucose levels and improved insulin sensitivity as measured by an insulin tolerance test, and significantly reduced fat content of liver and muscle. In mice treated with the LTA4H inhibitor, a reduction in MCP-1 expression was observed in the liver, as well as reduced F4/80 immunoreactivity as a marker of macrophage infiltration, in adipose tissue. Our data suggest that LTA4H inhibitors may be of use for type II diabetes and related metabolic diseases.
Embodiments of this invention are expected to find utility in treating any one or a combination of atopic dermatitis, contact dermatitis, acne (Alestas, et al., J. Mol. Med. 2006, 84(1): 75-87; Zouboulis, et al., Dermatology, 2005, 210(1): 36-8; Arch. Dermatol. 2003, 139(5): 668-70), myocardial infarction (Helgadottir, et al., Nat. Genet. 2006, 38(1): 68-74; Nat. Genet. 2004, 36(3): 233-9; Hakonarson, et al., JAMA 2005, 293(18): 2245-56), stroke (Helgadottir, et al., Nat. Genet. 2004, 36(3): 233-9; Barone, et al., Mol. Chem. Neuropathol. 1995, 24(1): 13-30), pain (Cunha, et al., Br. J. Pharmacol. 2003, 139(6): 1135-45; Hwang, et al., Proc. Natl. Acad. Sci. USA 2000, 97(11): 6155-60), itch (Andoh, et al., Eur. J. Pharmacol. 2006, 547(1-3): 59-64; Andoh et al., J. Investigativ. Dermatol. 2004, 123(1): 196-201); gingivitis (Emingil, et al., J. Periodontol. 2001, 72(8): 1025-31), uveitis (Liao, et al., Invest. Opthalmol. Vis. Sci. 2006, 47(4): 1543-9), bronchitis (Gompertz, et al., Eur. Respir. J. 2001, 17(6): 1112-9), allergic rhinitis, cystic fibrosis (Carpagnano, et al., Am. J. Respir. Crit. Care Med. 2003, 167(8): 1109-12), upper grastrointestinal cancer (Chen, et al., Curr. Cancer Drug Targets 2004, 4(3): 267-83; J. Natl. Cancer Inst. 2003, 95(14): 1053-61), and sepsis (Nakae, et al., Res. Commun. Chem. Pathol. Pharmacol. 1994, 83(2): 151-6, and 84(3): 271-81), Sjogren Larsson syndrome, Sjogren syndrome, skin burns, such as those due to sunburn or some other agent, and type II diabetes.
Examples of textbooks on the subject of inflammation include: 1) Gallin, J. I.; Snyderman, R., Inflammation: Basic Principles and Clinical Correlates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999; 2) Stvrtinova, V., et al., Inflammation and Fever. Pathophysiology Principles of Diseases (Textbook for Medical Students); Academic Press: New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W.B. Saunders Co., 1988; and 4) Stedman's Medical Dictionary.
Background and review material on inflammation and conditions related with inflammation can be found in articles such as the following: C. Nathan, Points of control in inflammation, Nature 2002, 420: 846-852; K. J. Tracey, The inflammatory reflex, Nature 2002, 420: 853-859; L. M. Coussens and Z. Werb, Inflammation and cancer, Nature 2002, 420: 860-867; P. Libby, Inflammation in atherosclerosis, Nature 2002, 420: 868-874; C. Benoist and D. Mathis, Mast cells in autoimmune disease, Nature 2002, 420: 875-878; H. L. Weiner and D. J. Selkoe, Inflammation and therapeutic vaccination in CNS diseases, Nature 2002, 420: 879-884; J. Cohen, The immunopathogenesis of sepsis, Nature 2002, 420: 885-891; D. Steinberg, Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime, Nature Medicine 2002, 8(11): 1211-1217.
Inflammation is due to or associated with any one of a plurality of conditions, such as asthma, chronic obstructive pulmonary disease (COPD), α1-antitrypsin (α1AT) deficiency, atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis, contact dermatitis, acne, myocardial infarction, stroke, pain, itch (pruritus), gingivitis, uveitis, bronchitis, allergic rhinitis, cystic fibrosis, upper gastrointestinal cancer, sepsis, Sjogren syndrome, Sjogren-Larssen syndrome, and skin burns, which are each characterized by excessive or prolonged inflammation at some stage of the disease.
Organ transplant rejection and autoimmune disease treatment with a cyclooxygenase-2 inhibitor and an LTA4H inhibitor are disclosed in WO1997/29774, U.S. Patent Appl. Publ. Nos. US2003/004191 and US2005/043355, and in U.S. Pat. Nos. 5,700,816, 6,407,140. LTA4H inhibitors are disclosed in U.S. Pat. Nos. 5,719,306, 6,506,876, 5,723,492, 5,585,492, and publication WO1996/11192. Cyclic and bicyclic diamino histamine-3 receptor antagonists are disclosed in U.S. Pat. No. 6,559,140. Certain indole derivative compounds are disclosed in U.S. Pat. No. 5,639,752. Benzothiazole and benzoxazole LTA4H modulators have been described in U.S. Patent Appl. Publ. Nos. US2005/0043378 and US2005/0043379, and by Grice et al. (Abstracts of Papers, 234th ACS National Meeting, Boston, Mass., United States, Aug. 19-23, 2007), Rao et al. (J. Pharmacol. Exp. Ther. 2007, 321(3), 1154-1160) and Whittle et al. (Br J. Pharmacol. 2008, 153, 983-991). In addition, diamine derivatives are described as LTA4H inhibitors in U.S. Patent Appl. Publ. No. 2007/0155726 and Intl. Patent Appl. Publ. No. WO2007/079078. Aryl-substituted bridged diamines are disclosed as LTA4H modulators in U.S. Provisional Pat. Appl. No. 60/984,126. Combinations of a cyclooxygenase-2 inhibitor and an LTA4H inhibitor for the treatment of inflammation and inflammation-related disorders are disclosed in U.S. Pat. No. 5,990,148 and in publication WO1996/41625. Nitrogenous derivatives have been disclosed in patent-related as well as in nonpatent-related publications, such as WO2008/016811; US2008/0057074; WO2006/002133; U.S. Pat. No. 6,316,490; U.S. Pat. No. 6,632,823; U.S. Pat. No. 6,432,976; WO2006/133802; WO2003/037904; EP 623621; EP 416521; S. Collin, J. Pharmacie de Belgique, 1991, 46(1) 55-66; P. Dostert, et al., European. J. Med. Chem., 1984, 19(2) 105-110; FR 2446823; U.S. Pat. No. 4,410,535; U.S. Pat. No. 4,352,802; U.S. Pat. No. 4,471,120; U.S. Pat. No. 4,424,358; U.S. Pat. No. 4,321,378; U.S. Pat. No. 4,329,466; U.S. Pat. No. 4,536,580; U.S. Pat. No. 4,273,778; U.S. Pat. No. 4,336,259; U.S. Pat. No. 4,544,660; U.S. Pat. No. 4,599,420; and U.S. Pat. No. 4,705,858. Certain compounds that contain 1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine moiety are described in Kennis et al., Bioorg & Med Chem. Lett., 2000, 10, 71-74. The synthesis of 1,2,3,4-tetrahydrothianaphtheno[3,2-c]pyridine is disclosed in Capps et al., J Am Chem. Soc., 1953, 75(3), 697-699. Certain tricyclic delta3-piperidines are described in U.S. Pat. No. 6,495,555. Certain thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amine compounds are disclosed in U.S. patent application Ser. No. 12/421,406. Synthesis of 4-methanesulfonyl-piperidin-1-ylmethyl is described in Intl. Pat. Appl. No. WO 2000/50391. However, there remains a need for potent LTA4H modulators with desirable pharmaceutical properties.
Certain fused bicyclic heteroaryl derivatives have been found in the context of this invention to have LTA4H-modulating activity. References cited throughout the written description are incorporated herein by reference.